Glioblastomas are the most common primary and malignant brain tumors. The standard therapy includes surgery and radiotherapy plus chemotherapy, with additional bevacizumab to block the angiogenesis in tumors. However, the ever-growing tolerance of glioblastomas to chemotherapeutic drugs impairs the clinical outputs of tumor treatment. The present study investigated the tolerance of glioblastomas to bevacizumab. Although bevacizumab resulted in direct anti-proliferation and pro-apoptosis effects on glioblastoma cells via downregulating the anti-apoptotic proteins and upregulating the pro-apoptotic proteins, tolerance was also encountered that was mainly caused by autophagy induction in tumor cells...

PURPOSE: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. The epigenetically active ribonucleoside analog 5-azacitidine is a new therapy option that changes tumor cell chromatin, which is frequently modified by methylation and deacetylation in malignant gliomas. METHODS: In vitro, we analyzed cell viability, cell apoptosis, and migration of human GBM cells. In vivo, we established subcutaneous and intracerebral GBM mouse models originating from U87MG, U373MG, and primary GBM cells as well as one patient-derived xenograft...

Background: Antiangiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev refractory glioblastoma. Methods: Twenty-eight patients with Bev refractory GBM were enrolled in a dose escalation study receiving from 240mg/m2 (cohort 1) to 670mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev...

Background: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained...

Angiogenesis plays a critical pathologic role in malignant gliomas. In the past few years, numerous studies using bevacizumab (BEV), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), have been conducted in patients with brain tumors. Current evidence suggests that such treatment produces favorable results in patients with recurrent glioblastoma multiforme (GBM), but is not associated with any benefits in newly diagnosed GBM and recurrent WHO grade III gliomas. Initial experience using BEV for management of central nervous system radiation necrosis demonstrated radiographic improvement in the majority of cases, but optimal dose and treatment duration in such cases still remain in question...

Malignant gliomas are the most common primary brain tumors and have devastatingly high mortality rates. Most recurrences are close to the surgical bed, despite adjuvant fractionated radiotherapy (FRT). Localized FRT to total dose of 60 Gy with concurrent and adjuvant temozolomide (TMZ) resulted in a statistically significant survival improvement of patients with newly diagnosed glioblastoma compared to those treated with FRT alone, and has emerged as the cornerstone of therapy. Despite this progress, long-term survival remains poor...

Management options for residual or recurrent glioblastoma multiforme (GBM) are limited despite advances in surgical, chemotherapeutic, and radiotherapeutic techniques. Stereotactic radiosurgery (SRS) is often beneficial in such cases providing improved survival of patients, but still remains underutilized as part of the multimodality management of malignant gliomas. During the last 20 years, 297 patients with histologically proven residual or recurrent GBM underwent Gamma Knife surgery in the University of Pittsburgh...

The diagnosis of glioblastoma (GBM) often carries a dismal prognosis, with a median survival of 14.6 months. A particular challenge is the diagnosis of GBM in the elderly population (age > 75 years), who have significant comorbidities, present with worse functional status, and are at higher risk with surgical treatments. We sought to evaluate the impact of current GBM treatment, specifically in the elderly population. The authors undertook a retrospective review of all patients aged 75 or older who underwent treatment for GBM from 1997 to 2016...

Rechallenge with temozolomide has been shown to be a valid option in selected patients with progressive glioblastoma. Herein, we assessed the efficacy of rechallenge with bevacizumab in glioblastoma patients progressing off therapy. We retrospectively identified and analyzed the characteristics of patients with glioblastoma rechallenged with a bevacizumab-based chemotherapy regimen after having received bevacizumab as first-line treatment in association with temozolomide radiochemotherapy or at recurrence in association with temozolomide, CCNU or irinotecan...

AIMS: We aimed to identify a clinically useful biomarker using DNA methylation-based information to optimize individual treatment of patients with glioblastoma (GBM). METHODS: A six-CpG panel was identified by incorporating genome-wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk-score model. Different validation sets of GBMs and lower-grade gliomas and different statistical methods were implemented for prognostic evaluation...

The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been treated with irinotecan 125 mg/m2 and bevacizumab 10 mg/kg every 2 weeks...

Glioblastoma multiforme (GBM) is a highly aggressive glial brain tumor with an unfavorable prognosis despite all current therapies including surgery, radiation and chemotherapy. One characteristic of this tumor is a strong synthesis of vascular endothelial growth factor (VEGF), an angiogenesis factor, followed by pronounced vascularization. VEGF became a target in the treatment of GBM, for example with bevacizumab or the tyrosine kinase inhibitor axitinib, which blocks VEGF receptors. To improve patients' prognosis, new targets in the treatment of GBM are under investigations...

Intercellular cell adhesion molecule 1 (ICAM-1; also known as CD54) is overexpressed in bevacizumab-resistant glioblastoma. In the present study, we tested our hypothesis that highly expressed ICAM-1 mediates glioblastoma's resistance to antiangiogenic therapy. We validated ICAM-1 overexpression in tumors resistant to antiangiogenic therapy using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. We also detected ICAM1 expression in most glioma stem cells (GSCs). We investigated the mechanism of ICAM-1 overexpression after bevacizumab treatment and found that ICAM-1 protein expression was markedly increased in a time-dependent manner in GSC11 and GSC17 cells under hypoxic conditions in vitro...

OBJECTIVE: The aim of this study was to report cases of medication-related osteonecrosis of the jaws (MRONJ) associated with targeted therapy (TT) with or without concomitant antiresorptive treatment, among the Copenhagen ONJ cohort, which includes all consecutive cases of MRONJ seen in Copenhagen. STUDY DESIGN: We retrospectively studied the treatment of 204 consecutive patients with MRONJ, seen between January 2010 and May 2016, to identify those associated with TT...

PURPOSE: To analyse feasibility, prognostic factors and patterns of recurrence after concurrent reirradiation and bevacizumab for recurrent high-grade gliomas. PATIENTS AND METHODS: Between 2009 and 2015, 35 patients (median 57-year-old; 21 men, 14 women) with WHO grade III (n=11) or grade IV (n=24) gliomas were included in this retrospective and consecutive single-centre study. All patients received bevacizumab (median number of treatments: 12) concomitant with reirradiation (median dose: 45Gy, median number of fractions: 18) for recurrence with median 22 months (range: 5...

Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM...